Previously, we discovered that neuropeptide Y (NPY), its Y2Rs and an endothelial dipeptidyl peptidase IV form a potent angiogenic system. In addition to NPY's main secretory pool in sympathetic nerves activated by stress, other non-neuronal sources were identified in ECs and platelets, contributing to ischemic angiogenesis and atherosclerosis. As adipose tissue actively remodels, in the last period we studied NPY's role in fat angiogenesis and growth. This led to discovery of adipogenic actions of NPY and the phenomenon of "stress-induced obesity." Chronic stress augmented high fat diet-induced obesity and metabolic syndrome (MetSyn) by stimulating angiogenesis, inflammation and de-novo adipogenesis through up-regulated NPYY2R system, predominantly in the abdominal fat due to locally produced glucocorticoids. Stress/NPY-induced angio/adipogenesis and obesity were prevented by intra-fat Y2R inhibition or deletion;this work offered new avenues for fat remodeling and anti-obesity/MetSyn therapies. What characterizes "stressed fat", how lasting are its effects on fat tissue and metabolic consequences, and which NPY-Y2R carrying cells are responsible for it - is unknown and will now be studied. Stress appears to target neurovascular niches which contain nerves, adipose stem cells (ASCs), ECs and immune cells, each expressing NPY or its Rs. "Stressed" ASCs show both increased adipogenic potential and upregulated NPY system. In human Y2Rpositive fat grafted into nude mice, elevated NPY induces vascularization and long-lasting graft survival. These and new data of epigenetic regulation of NPY, prompted us to hypothesize that stress epigenetically upregulates the NPY system in ASCs, increasing adipogenic potential of "stressed" fat, specifically abdominal, accelerating diet-induced obesity and MetSyn. Inhibition of Y2Rs or altering DNA methylation of these or other adipogenic genes - inhibits these processes. We will use genetically modified mice, transfer of fat/ASCs between stressed and non-stressed mice, state-of-the-art 3D fat imaging, genome-wide epigenetic analyses, and relate the results to changes in human ASCs, stressed in vitro or in vivo, in nude mice. PUBLIC HEALTH RELEVANCE: Obesity is on the rise and with it, the risk of cardiovascular diseases. Our previous work have showed that stress may play a role by stimulating fat growth directly through nerves, which secrete Neuropeptide Y, a chemical causing ingrowth of new vessels and fat expansion. Identifying cellular molecular mechanisms of stress actions may lead to better ways of prevention or treatment of obesity and cardiovascular diseases.